[R01] HIV-1 Reservoir and Host Cell Dynamics Over Twenty Years on ART: Reservoir Kinetics, Antigen-Specific T Cell Dynamics, and Model-Building
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2031-06-30
Importo max: 811.568 EUR
Paese: US
Descrizione
PROJECT SUMMARY/ABSTRACT
Despite the success of antiretroviral therapy (ART) in suppressing viral replication, no cure for HIV has been
found. This is because HIV persists in a reservoir comprised of intact, inducible HIV proviruses in CD4+ T cells
and, to a lesser degree, myeloid cells. A deeper, more quantitative understanding of the forces that sustain the
reservoir will allow us to engineer more effective HIV cure therapeutics. We know that the HIV reservoir decays
in the first ~7 years after ART initiation, but reservoir dynamics in the second decade and beyond are not well
characterized. Of the few individuals studied longitudinally out to 20 years, some experience continued reservoir
decay while others show signs of reservoir expansion. In this work, we will conduct a large, multi-decade, multi-
platform study of the dynamics of latently infected cells and host CD4+ T cells. We will use this data to estimate
the relative contributions of the biological factors that sustain the reservoir at different points in time after ART
initiation. We will test the hypothesis that the reservoir initially decays due to immune selection, after which the
reservoir’s persistence is largely driven by the kinetics of the most highly-expanded, infected clones. In the first
aim, we will characterize 20-year HIV reservoir trajectories using the intact proviral DNA assay in dozens of
people living with HIV (PWH) on ART and identify biological factors that differ between those with continued
decay and those with expansion in the second decade on ART. Biological factors examined include expansion
rates of underlying HIV-infected CD4s and uninfected memory CD4s, CMV serostatus, and sex. In the second
aim, we will quantify the contribution of antigen-specific clonal proliferation to overall memory (m)CD4+ T cell
persistence in a subset of PWH on long-term ART. To do this, we will first use the ViraFEST assay to identify T-
cell receptor (TCR)β sequences of mCD4+ T cells that proliferate in response to one of four viral antigens. Then
we will obtain longitudinal resting mCD4+ TCRβ and paired TCRαβ repertoires from the same individuals and
track each antigen-specific clone’s proliferative kinetics over 20 years on ART. We will model these thousands
of antigen-specific clone trajectories to provide insight into how antigen exposure shapes long-term persistence
of memory CD4+ T cells. In the third aim, we will refine, validate, and extend our stochastic model of HIV reservoir
dynamics to incorporate 20 years of ART data. First, we will generate empiric data on clone kinetics of CD4s
harboring intact and defective proviruses and uninfected mCD4s by performing near-full length sequencing and
mCD4+ TCR repertoire sequencing on longitudinal samples. We will use this data to refine and validate our
current model and extend its applicability to the first twenty years on ART, thus providing a comprehensive
framework to estimate the relative contributions of various forces, suc
Istituzione: JOHNS HOPKINS UNIVERSITY
PI: Annukka Aida Rose Antar
Progetto: 1R01AI194979-01A1
Settori: National Institute of Allergy and Infectious Diseases
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